由于缺乏类似于心肌损伤和炎症反应的人源化心脏模型，目前针对心肌缺血/再灌注（I/R）损伤的治疗药物探索受到限制。在此，我们利用人诱导多能干细胞（hiPSC）开发心室心脏类器官，并通过缺氧/复氧（H/R）模拟缺血性心脏病损伤，从而导致心肌细胞凋亡增加、氧化应激升高、形态结构破坏和心跳幅度降低。 RNA-seq 揭示了 I 型干扰素 (IFN-I) 在这种 I/R 损伤模型中的潜在作用。然后我们引入 THP-1 细胞并揭示单核细胞/巨噬细胞和 H/R 诱导的心室心脏类器官之间的炎症反应。此外，我们证明 Anifrolumab 是 FDA 批准的 IFN-I 受体拮抗剂，可有效降低 IFN-I 分泌和相关基因表达，减轻共培养系统中 H/R 诱导的炎症和氧化应激。这项研究推进了人类心脏类器官炎症反应引起的心肌 I/R 损伤的建模，为临床前研究和药物筛选提供了可靠的平台。© 2024 作者。北京干细胞与再生医学研究院和John Wiley联合出版的《细胞增殖》

Current therapeutic drug exploring targeting at myocardial ischemia/reperfusion (I/R) injury is limited due to the lack of humanized cardiac models that resemble myocardial damage and inflammatory response. Herein, we develop ventricular cardiac organoids from human induced pluripotent stem cells (hiPSCs) and simulate I/R injury by hypoxia/reoxygenation (H/R), which results in increased cardiomyocytes apoptosis, elevated oxidative stress, disrupted morphological structure and decreased beat amplitude. RNA-seq reveals a potential role of type I interferon (IFN-I) in this I/R injury model. We then introduce THP-1 cells and reveal inflammatory responses between monocytes/macrophages and H/R-induced ventricular cardiac organoids. Furthermore, we demonstrate Anifrolumab, an FDA approved antagonist of IFN-I receptor, effectively decreases IFN-I secretion and related gene expression, attenuates H/R-induced inflammation and oxidative stress in the co-culture system. This study advances the modelling of myocardial I/R injury with inflammatory response in human cardiac organoids, which provides a reliable platform for preclinical study and drug screening.© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.